Polymeric Paste Compositions for Drug Delivery

ABSTRACT

This invention provides compositions for controlled localized release of one or more drugs within a subject. More particularly, described herein are compositions comprising a hydrophobic water-insoluble polymer, a low molecular weight biocompatible glycol, and one or more drugs. The compositions described herein may also optionally include a di-block copolymer and/or a swelling agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/619,427, filed Dec. 4, 2019, now U.S. Pat. No. 11,167,034, which is aU.S. National Stage entry of International Application Serial No.PCT/CA2018/050714, filed Jun. 13, 2018, which claims the benefit of U.S.Provisional Patent Application Ser. No. 62/518,800 filed on 13 Jun.2017, entitled “POLYMERIC PASTES FOR DRUG DELIVERY”.

FIELD OF THE INVENTION

This invention relates to biodegradable polymeric pastes suitable fordrug delivery. More particularly, the invention relates to injectablepolymeric pastes that release drugs in a controlled manner.

BACKGROUND OF THE INVENTION Prostate Cancer

The anatomy and pathogenesis of prostate cancer (PCa) lends itself tolocalized treatment modalities. Low risk early-stage localized PCa oftenhas a low long-term likelihood of progression and metastases, andtreatments such as surgery or radiation may unnecessarily exposepatients to the risks of treatment without a concomitant meaningfulcancer-specific benefit. While surgery and radiation lead to excellentlong-term cancer-free rates, it is estimated that PCa-related death willbe prevented in only one out of 5 to 48 patients undergoingtreatment^(1,2). To minimize the risk of ‘overtreatment’, activesurveillance (AS) without immediate treatment has become an increasinglyutilized option for some men with appropriate low to intermediate-riskcancer characteristics.

Large population-based studies evaluating outcomes for PCa based onclinical and pathological parameters have established well defined PCarisk categories³. Low risk PCa, defined as cT1-cT2a, Gleason score ≤6,PSA <10, is unlikely to progress and require radical treatment, and isreadily amenable to AS. AS for low and low-tier intermediate risk PCahas demonstrated favourable outcomes, and can spare up to 50% of menfrom radical treatment at 5 years⁴. AS has provided insight into thenatural history of lower risk PCa and also addresses the populationhealth concerns arising from PCa over-detection and overtreatment.Triggers to come off AS and proceed to definitive intervention includerises in serum PSA values, histological progression on biopsy,development of lower urinary tract symptoms, or patient anxiety onfollow up.

While AS aims to minimize the risk of overtreatment, it relies on theassumption that the cancer will not metastasize and requires biopsiesevery 1-2 years. Taking this strategy can cause anxiety over living withan untreated cancer and leads to delayed whole-gland treatment(radiation or surgery) in 30-40% of patients⁵. For some men withlow-risk and intermediate-risk PCa, AS may be undesirable, yet theshort-term and long-term complications associated with surgery andradiation present unacceptable risks. Moreover, any benefits of curativetreatment with surgery or radiotherapy are small at durations of followup of less than 10 years, and are hence associated with adverse effectson quality of life without near-term benefits in disease control^(6, 7).

For this reason, there has been a growing interest in minimally invasivefocal therapies for PCa⁸⁻¹⁰. The dual goals are to eradicate a focalarea of cancer and maintain normal urinary, sexual, and bowel function.Several minimally invasive ablation methods, such ascryotherapy^(11, 12) and high-intensity focused ultrasound (HIFU)¹³,have been developed and are currently FDA approved. These are, however,ablative therapies that kill benign and cancer cells indiscriminatelyand can lead to erectile dysfunction and fistulae.

Upper Tract Urothelial Carcinoma Urothelial carcinomas (UCs) may occurin the lower urinary zones (bladder or urethra) or in the upper urinarytract (UUT: pyelocaliceal cavities and ureter)¹⁴. Over 90% of UCs arelocated in the bladder with under 10% occurring in the upper tract(UTC). Patients with bladder cancer are usually diagnosed with earlystage disease and the cancer confined to the superficial urothelium.This is partly due to the easy access of diagnostic equipment via theurethra. However, many patients with UTCs are not diagnosed early andmay have already progressed to invasive disease. Staging of UTCs mayalso be difficult as the tissue is fragile with only limited musculatureso that biopsies do not always accurately describe the disease level.

Once diagnosed, radical nephroureterectomy (RNU) with bladder-cuffremoval is considered the standard treatment of UTC^(15, 16). Thisprocedure involves full removal of the kidney, the ureter and thebladder cuff. Tumor cell spillage may be a problem with such procedures.Furthermore, many patients are not candidates for this treatment. Somepatients with low-risk disease, may be offered a more conservativetreatment such as endoscopic ablation or segmental removal¹⁴. Clearly,with later diagnosis, the prognosis for these patients with UTC is poor.Chemotherapeutic options are limited for these patients especiallybecause cisplatin based regimens are associated with nephrotoxicity,which may be exacerbated, when one kidney is removed. Other drugs usedto treat bladder cancer such as Mitomycin C and Gemcitabine may have apreferred toxicity profile. However, when used to treat bladder cancerthese drugs may be delivered at high concentrations intravesically(directly into the bladder) so that a 2 hour retention allows reasonabledrug uptake into the tissues after tumor resection. More recently, thedrug docetaxel is under investigation as a chemotherapeutic option totreat bladder cancer locally and UTC by systemic delivery. Thecombination of gemcitabine and docetaxel, is also being studied as animprovement to using either drug alone¹⁷.

Because the UUT tissues cannot be treated locally with a drug solution(the pelvis is accessible but drug solutions would quickly wash into thebladder) one company (Urogen™) has developed a gel formulation ofmitomycin called Mitogel. This gel undergoes a thermos-reversible geltransition in the body so may be injected as a liquid to form a semisolid gel in the pelvis of the kidney. The pluronic-based gel dissolvesslowly, but allows for some retention of the drug in the tissues at thetarget site.

Background Chronic Scrotal Pain

Chronic scrotal contents pain (CSCP) is a common entity afflicting menof all ages and has been reported to peak in the mid to latethirties^(18, 19). A study conducted in Switzerland reported anestimated incidence of 350-400 cases per 100,000 men per year²⁰. CSCP isan intermittent or constant, unilateral or bilateral pain involving thetestes, epididymis, vas deferens or para-testicular structures of atleast three months duration²¹. The etiology for CSCP is varied and isdivided into scrotal and extra-scrotal causes. Extra-scrotal causesinvolve irritation of the ilioinguinal, genitofemoral or pudendalnerves. This can include inguinal hernias/hernia repairs, urolithiasis,or retroperitoneal tumors among many others. Causes within the scrotuminclude infection, prior scrotal surgery, post vasectomy pain oranatomic abnormalities.

Effective treatment options for CSCP are limited and data consistsprimarily of non-randomized, small studies. Conservative therapiesinclude rest, ice and scrotal supports along with pain education andcounselling. There is no standardized protocol for treatment²¹, but themainstay of medical therapy involves nonsteroidal anti-inflammatorydrugs (NSAIDs) with tricyclic antidepressants or gabapentin asalternatives²². Antibiotics may be trialed, if epididymo-orchitis is inthe differential diagnosis. Beyond this, non-invasive options includepelvic floor physiotherapy, acupuncture or transcutaneous electricalnerve stimulation (TENS), but these are not associated with frequent ordurable control of CSCP. Lidocaine combined with steroid injectionsshort term relief for men with testicular pain²³. A case report from2009 indicated success with sacral nerve stimulation though no furtherstudies have validated this response²⁴. In 2012 a case series reportedon treatment of chronic orchialgia using pulsed radiofrequency ablation,but again are not associated with frequent or durable control²⁵. Anopen-label trial from 2014 on spermatic cord injections with Botulinumtoxin showed modest results for up to 3 months, but with limited effectat six-month follow up²⁶. A very recent study reported that a subset ofmen with chronic testicular pain can benefit from excess doses ofvitamin B12 and testosterone, but this type of treatment may beassociated with increased risk of prostate cancer associated withtestosterone treatment²⁷.

Surgical management is reserved for those who have persistent scrotalpain despite adequate trials of conservative and medical therapies. Inthe past, surgery for scrotal pain has focused on the area of thescrotum thought to be the source of pain. Epididymectomy, vasovasostomy,varicocelectomy and orchiectomy have all been attempted, but areinvasive, associated with risk of loss of the testicle, and have lowlong-term pain control. In a study by Polackwich et al., vasovasostomyor vasoepididymostomy, in men with post vasectomy pain syndrome,provided a degree of relief in 82% of patients²⁸. Epididymectomy forpost vasectomy pain was studied by Hori et al. and produced a meandecrease in pain score by 67%²⁹. Epididymectomy for epididymal pain ledto significant reductions in pain which were more pronounced forepididymal cysts compared to chronic epididymitis³⁰.

In contrast to anatomically based surgical interventions, microsurgicalspermatic cord denervation (MSCD) provides effective pain relief formultiple sources of intrascrotal pain in men who respond to initialspermatic cord block. Multiple studies have shown results for MSCD withcomplete response rates in approximately 70 percent of patients (range49-96%)³¹⁻³⁵. MSCD can be utilized as an initial surgical managementtool or after other surgical interventions have failed³⁶. As with othersurgical procedures, MSCD does involve use of a general anesthetic andthere are risks of testicular atrophy or loss of testicle, as well aspersistent pain despite and expensive surgical procedure.

Overall, the treatment of CSCP is challenging due to its multifacetedetiology and indistinct presentation, which imposes a significant burdenon the patient and physician. Many patients with CSCP are left withuntreated pain, seeking consultation with multiple physicians, loss ofwork, and risk of narcotic exposure³¹. As highlighted in the EuropeanUrological Association 2013 guidelines, chronic scrotal pain is “oftenassociated with negative cognitive, behavioural, sexual or emotionalconsequences.”³⁷. A study from 2011 found that men with orchialgia haddecreased scores in orgasmic function, intercourse satisfaction andsexual desire compared to men with no pain. Overall sexual satisfactionand International Index of Erectile Function scores were alsosignificantly lower in this group³⁸. Thus, there remains an unmetclinical need for effective delivery of therapeutics in the managementof CSCP.

To provide pain relief for CSCP, spermatic cord block is a valuabletreatment option. The single local injection of lidocaine to break thepain cycle³⁹ is suggested at a dose of 100 mg (10 mL of 1% lidocaine)for peripheral nerve block⁴⁰. This regional delivery of lidocaine ischaracterized by a quick onset (3 min) and of short duration (60-120min). A maximum dose of 4.5 mg/kg of lidocaine alone can be used and ifepinephrine is added this amount can be further increased to 6 mg/kg.Epinephrine acts as a vasoconstrictor, slows the systemic absorption oflidocaine and prolongs its duration of action^(41, 42).

Instead of using epinephrine, which produces the common unwantedsympathomimetic side effects including vasoconstriction and reducedblood flow, it is preferred to use a drug carrier for lidocaine, whichresides locally and releases small amounts of the drug over a moreextended period of time.

In traditional chemotherapy, drugs are delivered systemically followingresection surgery or to treat metastatic disease. However, to treatlocal tumors, a better method might be to deliver a controlled releasedrug formulation to the disease site. Currently, there are few suchformulations available, often because the target tissue is difficult toaccess and locally delivered solutions of drugs are cleared ratherquickly from the area, offering little efficacy. Certain tissues (likethe prostate or upper urothelial tract) are routinely accessed inpatients (needle biopsy for prostate or by endoscopy for UUT) and offerpotential sites for local drug delivery. For the prostate, where thetarget tissue is confined to an organ with defined boundaries, aninjectable, slow release polymeric paste might be suitable. Deliveringdrugs directly to the pelvis of the kidney to treat UTC is problematicbecause the ureter cannot be blocked by a polymeric paste for a longtime. Delivery to this area may require using an injectable that breaksup or dissolves over a reduced time-frame so that urine may flow butsome the drug loaded formulations remains to allow for local tissueuptake.

Injectable Polymeric Paste

Drugs are normally delivered orally or by injection to allow systemicuptake and circulation to most parts of the body. For many drugs thisroute of administration is ideally suited, for example, insulin fordiabetes or statins for heart disease. However, many diseases arelocalized and the preferred method is to deliver the drug directly tothe site of action. For example, painkillers for chronic localized pain,anticancer drugs for local tumors and anti-arthritic drugs to relievesymptoms of arthritis and joint pain. Accordingly, there have beennumerous attempts to design locally injectable systems to deliver drugsto specific body sites. This targeted approach may also minimizesystemic toxicity often associated with conventional methods ofdelivering drugs. The intravenous delivery of anticancer drugs oftencauses severe side effects and systemic toxicities usually limit drugdose. Local polymeric drug delivery systems could mitigate systemic sideeffects and allow for the delivery of high local doses.

PLGA is a common constituent of polymeric drug delivery systems. It isan FDA-approved biopolymer of lactic acid (D,L-LA) and glycolic acid(GA) and has been used both as a drug delivery carrier and as a scaffoldfor tissue engineering^(43, 44). The degradation of PLGA depends on manyfactors including, but not limited to, the ratio of LA to GA,crystallinity, weight average molecular weight of the polymer, shape ofthe matrix, and type and amount of drug incorporated^(45, 46). The ratioof LA to GA is a major player in degradation and polymers with a higheramount of the more hydrophilic GA generally degrade faster. Thedegradation products of PLGA are the hydrolysis products LA and GA. Bothcan enter the citric acid cycle and can be excreted as water and carbondioxide, or in the case of GA, mainly excreted unchanged by thekidney⁴⁶. Minor toxicities like transient inflammation have beenreported for some PLGA based implants⁴⁷, but they likely reflectincreased exposure times and reduced clearance of the degradationproducts.

Injectable, drug loaded polymeric pastes are attractive for local drugdelivery because ultrasound or MRI-guided systems allow pinpointaccuracy in directing a needle or catheter system to a target area.Others have described injectable liquids (e.g., Atrigel™)⁴⁸ composed ofan organic solvent like acetone or polyvinyl-pyrrolidone and a drug thatwhen injected into the body solidified as the solvent dissolved away.Such a system is flawed because introducing an organic solvent intopotentially sensitive tissue areas may induce unwanted local toxicity.Local drug delivery systems ranging from drug loaded polymeric coatingsof stents, injectable microspheres⁴⁹, perivascular films⁵⁰ andinjectable polymeric pastes have been described⁵¹. In these examples,the antiproliferative drug paclitaxel was used to inhibit proliferativeevents associated with restenosis, cancer and arthritis.

An early polymeric paste system described in the literature was based ona blend of polycaprolactone and methoxypolyethylene glycol that wasinjectable (molten) at above body temperatures, but set to an implant at37° C. to release drug⁵². The implant was brittle and hard and the hightemperature delivery was inappropriate for the injection into sensitivelocations. Injectable paclitaxel-loaded polymeric paste made from amixture of a triblock copolymer and methoxypolyethylene glycol that wasinjectable at room temperature and formed a solid implant in vivo hasalso been described⁵¹. This paste performed poorly in so far as therelease rate of the drug paclitaxel and other hydrophobic drugs was tooslow to achieve adequate tissue levels of active drug and thedegradation profile of the polymer was too long potentially interferingwith re-treatment injections. The inclusion of diblock copolymers ofvarious compositions in solid (not paste) microspheres has beenpreviously described⁴⁹. In this case, the dissolution of the diblockfrom the microspheres allowed for increased hydrophobic drug release aswell as opening of the matrix to water and enhanced degradation.Microsphere formulations are quite different to pastes. They do not flowunder injection so must be injected in a liquid suspension. As such,they can disperse easily from a targeted tissue area.

SUMMARY OF THE INVENTION

This invention relates to improved polymeric pastes for controlled drugdelivery. The compositions described herein allow for the formulationand injection of paste mixtures into the body of a subject whereby thepaste mixture may form an implant at a localized site. In one aspect,the present invention provides for controlled drug release frompolymeric paste delivery systems by using selected low-viscositywater-insoluble polymers to adjust the viscosity of the pasteformulation and regulate release rates of drug(s) payload. The paste maybe manufactured from simple polymers that form soft-hydrogel-likeimplants, which may degrade quickly where needed and the release of thedrug and/or drug combinations may be controlled. This invention is basedon the surprising discovery that only defined ratios and compositions ofPEG and PLGA can be used effectively to form a waxy drug deliverydeposit in vivo. Furthermore, it was discovered that the addition of adiblock copolymer may further control the release or fine tune therelease of drug from the composition in situ.

Provided herein are non-solvent based, biodegradable polymeric pasteswith controlled drug release properties. Furthermore, some of the pastecompositions described herein have a low enough viscosity for injection,but set in vivo to a more solid formulation to allow controlled releaseby drug diffusion. Alternatively, the inclusion of a mucoadhesiveswelling agent may further slow down the wash out time of theformulation for bladder uses.

When placed in an aqueous environment such as a body compartment, thelow molecular weight biocompatible glycol can dissolve out of the matrixand the hydrophobic water-insoluble polymer can partially solidify in asemi-hydrated state that renders the implant waxy. The low molecularweight biocompatible glycols used herein are water-soluble polymer, butmay not dissolve entirely out of the matrix over the lifetime of theimplant, which may result in a waxy form. A further aspect of theinvention includes compositions comprising a low molecular weightbiocompatible glycol; a hydrophobic water-insoluble polymer; a drug; andoptionally, a biocompatible diblock co-polymer such that the compositionis a semi-solid at temperatures at or about room temperature and arecapable of being injected into a subject through a syringe. This aspectof the invention has the advantage of being soft, comfortable,non-compressing of tissues whilst providing long-term, controlledrelease of a drug at a specific site of injection in a subject.

This invention also provides methods for using the aforementionedcompositions to form implants in vitro and in vivo. In vivomethodologies include injection of the composition to a site in asubject's body where the drug-containing implant is formed.

This invention also provides injection devices containing an implantforming composition according to this invention.

In a first aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having an inherentviscosity (IV) of about 0.15 to about 0.5 dL/g; (b) a low molecularweight biocompatible glycol; with a molecular weight at or below 1,450Daltons; and (c) one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having an inherentviscosity (IV) of about 0.15 to about 0.55 dL/g; (b) a low molecularweight biocompatible glycol; with a molecular weight at or below 1,450Daltons; and (c) one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having an inherentviscosity up to and including about 0.55 dL/g; (b) a low molecularweight biocompatible glycol; with a molecular weight at or below 1,450Daltons; and (c) one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having an inherentviscosity up to an including about 0.50 dL/g; (b) a low molecular weightbiocompatible glycol; with a molecular weight at or below 1,450 Daltons;and (c) one or more drug compounds or pharmaceutically acceptable salt,solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight up to and including about 60,000 Daltons; (b) a low molecularweight biocompatible glycol; with a molecular weight at or below 1,450Daltons; and (c) one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight up to and including about 76,000 Daltons; (b) a low molecularweight biocompatible glycol; with a molecular weight at or below 1,450Daltons; and (c) one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 4,300 daltons and about 60,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 4,200 daltons and 76,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 3,200 daltons and 80,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 2,200 daltons and 76,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 2,200 daltons and 70,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a composition, the compositionincluding: (a) a hydrophobic water-insoluble polymer having a molecularweight between about 2,200 daltons and 60,000 Daltons; (b) a lowmolecular weight biocompatible glycol; with a molecular weight at orbelow 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof.

In a further aspect, there is provided a pharmaceutical compositioncomprising a compositions as described herein, together with apharmaceutically acceptable diluent or carrier.

In a further aspect, there is provided a use of a composition asdescribed herein, for the manufacture of a medicament.

In a further aspect, there is provided a use of a composition asdescribed herein, for the treatment of a medical condition for which thedrug is used.

In a further aspect, there is provided a composition as describedherein, for use in the treatment of a medical condition.

In a further aspect, there is provided a commercial package comprising:(a) composition as described herein; and (b) instructions for the use.

The composition may further include a di-block copolymer. Thecomposition may further include a swelling agent. The composition mayfurther include a di-block copolymer and a swelling agent.

The hydrophobic water-insoluble polymer may have an inherent viscosity(IV) of about 0.15 to about 0.5 dL/g is polylactic-co-glycolic acid(PLGA). The hydrophobic water-insoluble polymer may have an inherentviscosity (IV) of about 0.15 to about 0.25 dL/g ispolylactic-co-glycolic acid (PLGA). The hydrophobic water-insolublepolymer may have an inherent viscosity (IV) of about 0.25 to about 0.5dL/g is polylactic-co-glycolic acid (PLGA). The hydrophobicwater-insoluble polymer may have an inherent viscosity (IV) of about0.15 to about 0.55 dL/g is polylactic-co-glycolic acid (PLGA). Thehydrophobic water-insoluble polymer may have an inherent viscosity (IV)of about 0.15 to about 0.60 dL/g is polylactic-co-glycolic acid (PLGA).The hydrophobic water-insoluble polymer may have an inherent viscosity(IV) of about 0.10 to about 0.5 dL/g is polylactic-co-glycolic acid(PLGA). The hydrophobic water-insoluble polymer may have an inherentviscosity (IV) of about 0.10 to about 0.6 dL/g is polylactic-co-glycolicacid (PLGA). The hydrophobic water-insoluble polymer may have aninherent viscosity (IV) of about 0.15 to about 0.45 dL/g ispolylactic-co-glycolic acid (PLGA). The hydrophobic water-insolublepolymer may have an inherent viscosity (IV) at of below about 0.3 dL/gis polylactic-co-glycolic acid (PLGA).

The hydrophobic water-insoluble polymer may have a molecular weightbetween about 2,200 daltons and 70,000 Daltons. The hydrophobicwater-insoluble polymer may have a molecular weight between about 4,300daltons and 60,000 Daltons. The hydrophobic water-insoluble polymer mayhave a molecular weight between about 4,200 daltons and 60,000 Daltons.The hydrophobic water-insoluble polymer may have a molecular weightbetween about 4,300 daltons and 70,000 Daltons. The hydrophobicwater-insoluble polymer may have a molecular weight between about 4,300daltons and 75,000 Daltons. The hydrophobic water-insoluble polymer mayhave a molecular weight between about 4,300 daltons and 50,000 Daltons.The hydrophobic water-insoluble polymer may have a molecular weightbetween about 3,300 daltons and 60,000 Daltons. The hydrophobicwater-insoluble polymer may have a molecular weight between about 2,300daltons and 60,000 Daltons.

The PLGA may have a ratio of lactic acid (LA):glycolic acid (GA) at orbelow 75:25. The PLGA may have a ratio of lactic acid (LA):glycolic acid(GA) at or below 65:35. The PLGA may have a ratio of lactic acid(LA):glycolic acid (GA) at or below 50:50. The PLGA may have a ratio oflactic acid (LA):glycolic acid (GA) of between 50:50 and 75:25. The PLGAmay have a ratio of lactic acid (LA):glycolic acid (GA) at or below85:15.

The hydrophobic water-insoluble polymer may have an inherent viscosity(IV) of about 0.15 to about 0.3 dL/g. The hydrophobic water-insolublepolymer may have an inherent viscosity (IV) of about 0.15 to about 0.25dL/g.

The low molecular weight biocompatible glycol may have a molecularweight between about 76 Daltons and about 1,450 Daltons. The lowmolecular weight biocompatible glycol may have a molecular weightbetween about 300 Daltons and about 1,450 Daltons. The low molecularweight biocompatible glycol may have a molecular weight between about 76Daltons and about 900 Daltons. The low molecular weight biocompatibleglycol may have a molecular weight between about 300 Daltons and about900 Daltons.

The low molecular weight biocompatible glycol may be selected fromPolyethylene glycol (PEG), methoxypolyethylene glycol (mePEG) andpropylene glycol. The low molecular weight biocompatible glycol may bePEG and mePEG. The PEG or mePEG may have an average molecular weight ofbetween 300 Daltons and 1,450 Daltons.

The composition may include a hydrophobic water-insoluble polymer havingan inherent viscosity (IV) of about 0.15 to about 0.5 dL/g is PLGAhaving a LA:GA ratio of 50:50 and a low molecular weight biocompatibleglycol is PEG or mePEG with a molecular weight of about 300 Daltons toabout 1,450 Daltons. The composition may include a hydrophobicwater-insoluble polymer having an inherent viscosity (IV) of about 0.15to about 0.5 dL/g is PLGA having a LA:GA ratio of 65:35 and a lowmolecular weight biocompatible glycol is PEG or mePEG with a molecularweight of about 300 Daltons to about 1,450 Daltons. The composition mayinclude a hydrophobic water-insoluble polymer having an inherentviscosity (IV) of about 0.15 to about 0.5 dL/g is PLGA having a LA:GAratio of 75:25 and a low molecular weight biocompatible glycol is PEG ormePEG with a molecular weight of about 300 Daltons to about 1,450Daltons. The composition may include a hydrophobic water-insolublepolymer having an inherent viscosity (IV) of about 0.15 to about 0.5dL/g is PLGA having a LA:GA ratio at or below 75:25 and a low molecularweight biocompatible glycol is PEG or mePEG with a molecular weight ofabout 300 Daltons to about 1,450 Daltons. The composition may include ahydrophobic water-insoluble polymer having an inherent viscosity (IV) ofabout 0.15 to about 0.5 dL/g is PLGA having a LA:GA ratio of 50:50 and alow molecular weight biocompatible glycol is PEG or mePEG with amolecular weight of about 300 Daltons to about 900 Daltons.

The ratio of PEG or mePEG to PLGA may be between about 80%:20% and about40%:60%. The ratio of PEG or mePEG to PLGA may be between about 70%:30%and about 40%:60%. The ratio of PEG or mePEG to PLGA may be betweenabout 80%:20% and about 50%:50%. The ratio of PEG or mePEG to PLGA maybe between about 60%:40% and about 40%:60%. The ratio of PEG or mePEG toPLGA may be between about 60%:40% and about 50%:50%.

The low molecular weight biocompatible glycol may be PEG 300. The lowmolecular weight biocompatible glycol may be PEG 600. The low molecularweight biocompatible glycol may be PEG 900.

The di-block copolymer may be between 13% and 26% of the total pastepolymer, wherein the di-block copolymer substitutes for hydrophobicwater-insoluble polymer. The di-block copolymer may be between 13% and26% of the total paste polymer. The di-block copolymer may be between10% and 30% of the total paste polymer, wherein the di-block copolymersubstitutes for hydrophobic water-insoluble polymer. The di-blockcopolymer may be between 5% and 40% of the total paste polymer, whereinthe di-block copolymer substitutes for hydrophobic water-insolublepolymer.

The di-block copolymer may have one hydrophobic monomer and onehydrophilic monomer.

The hydrophilic monomer may be selected from: PEG; and MePEG; and thehydrophobic monomer may be selected from: PLGA; polylactic acid (PLA);Poly-L-lactic Acid (PLLA); and Polycaprolactone (PCL). The hydrophilicmonomer may be selected from: PEG; and MePEG; and the hydrophobicmonomer may be selected from: polylactic acid (PLA); Poly-L-lactic Acid(PLLA); and Polycaprolactone (PCL). The hydrophilic monomer may beselected from: PEG; and MePEG; and the hydrophobic monomer may beselected from: PLGA; polylactic acid (PLA); and Poly-L-lactic Acid(PLLA). The hydrophilic monomer may be MePEG; and the hydrophobicmonomer may be PLGA. The hydrophilic monomer may be PEG; and thehydrophobic monomer may be PLLA. The hydrophilic monomer may be PEG; andthe hydrophobic monomer may be PLGA. The di-block copolymer may beamphiphilic. The di-block copolymer may be PLLA-mePEG. The di-blockcopolymer may be PLLA-PEG. The di-block copolymer may be PLA-mePEG. Thedi-block copolymer may be PLA-PEG.

The one or more drug compounds or pharmaceutically acceptable salt,solvate or solvate of the salt thereof may be selected from one or moreof the following categories: anti-cancer drugs; anti-inflammatoryagents; anti-bacterial; anti-fibrotic; and analgesic. The one or moredrug compounds or pharmaceutically acceptable salt, solvate or solvateof the salt thereof may be hydrophobic. The one or more drug compoundsor pharmaceutically acceptable salt, solvate or solvate of the saltthereof may be hydrophilic.

The anti-cancer drug may be selected from one or more of the following:Actinomycin; All-trans retinoic acid; Azacitidine; Azathioprine;Bleomycin; Bortezomib; Carboplatin; Capecitabine; Cisplatin;Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Docetaxel;Doxifluridine; Doxorubicin; Epirubicin; Epothilone; Etoposide;Fluorouracil; Gemcitabine; Hydroxyurea; Idarubicin; Imatinib;Irinotecan; Mechlorethamine; Mercaptopurine; Methotrexate; Mitoxantrone;Oxaliplatin; Paclitaxel; Pemetrexed; Teniposide; Tioguanine; Topotecan;Valrubicin; Vemurafenib; Vinblastine; Vincristine; Vindesine; andVinorelbine.

The anesthetic drug may be a local anesthetic selected from one or moreof the following: Procaine; Benzocaine; Chloroprocaine; Cocaine;Cyclomethycaine; Dimethocaine/Larocaine; Piperocaine; Propoxycaine;Procaine/Novocaine; Proparacaine; Tetracaine/Amethocaine; Articaine;Bupivacaine; Cinchocaine/Dibucaine; Etidocaine; Levobupivacaine;Lidocaine/Lignocaine/Xylocaine; Mepivacaine; Prilocaine; Ropivacaine;and Trimecaine. The anesthetic drug may be a local anesthetic selectedfrom one or more of the following: Procaine; Benzocaine; Chloroprocaine;Cyclomethycaine; Dimethocaine; Piperocaine; Propoxycaine; Procaine;Proparacaine; Tetracaine; Articaine; Bupivacaine; Cinchocaine;Etidocaine; Levobupivacaine; Lidocaine; Mepivacaine; Prilocaine;Ropivacaine; and Trimecaine. The anesthetic drug may be Lidocaine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the viscosity of polymeric pastes with different weightratios of PLGA, PEG and diblock copolymer.

FIG. 2 shows the release of PEG300™ from several polymeric pastemixtures.

FIGS. 3A and 3B show the release of docetaxel at 4%, bicalutamide at 4%,and VPC-27 at 10% (FIG. 3A) and 4% (FIG. 3B) from PEG:PLGA (50:50)polymeric pastes.

FIGS. 4A to 4C show the release of docetaxel (FIG. 4A), bicalutamide(FIG. 4B), and VPC-27 (FIG. 4C) from PEG:PLGA:Diblock polymeric pastes(57:37:13 or 50:24:26).

FIG. 5 shows the release of docetaxel at 0.25%, bicalutamide at 4%, andVPC-27 at 4% from PEG:PLGA:Diblock polymeric pastes (57:37:13 w/w %).

FIGS. 6A to 6D show the effect of varying PLGA:Diblock ratios (FIG. 6A)43%:7%, (FIG. 6B) 37%:13%, (FIG. 6C) 31%:19% (FIG. 6D) 25%:25% on therelease rates of docetaxel (0.5%), bicalutamide (4%), and VPC-27 (4%)from PEG:PLGA:Diblock pastes.

FIGS. 7A to 7C show the release of docetaxel (FIG. 7A), bicalutamide(FIG. 7B), and VPC-27 (FIG. 7C) from PEG:PLGA polymeric pastes (63:37 or76:24).

FIG. 8A to 8C show the release of docetaxel (1%), bicalutamide (4%), andVPC-27 (4%) from PEG:PLGA polymeric pastes (50:50 (FIG. 8A) or 55:45(FIG. 8B) or 60:40 (FIG. 8C)).

FIG. 9 shows the release of rapamycin (1%), docetaxel (1%), and VPC-27(4%) from PEG:PLGA:Diblock polymeric pastes (50:37:13 w/w %).

FIGS. 10A and 10B show the release of Cephalexin (FIG. 10A) 2% and (FIG.10B) 4%, 6%, 8% and 10% from PEG:PLGA:Diblock polymeric paste (50:37:13w/w %).

FIGS. 11A and 11B show the release of lidocaine from various pasteshapes (cylinder, crescent and hemisphere (FIG. 11A)) and at differentlidocaine concentrations (2%, 4%, 6%, 8% and 10% (FIG. 11B)) fromPEG:PLGA:Diblock polymeric paste (50:37:13 w/w %).

FIGS. 12A to 12C show the release of 1% docetaxel (FIG. 12A), 4%Enzalutamide (FIG. 12B), or 4% VPC-27 (FIG. 12C) from PEG:PLGA:Diblockpolymeric pastes (63:37 w/w % or 50:37:13 w/w %).

FIG. 13 shows the solubilization of docetaxel, bicalutamide, or VPC-27by diblock copolymer (molecular weight 3333, PLLA 40%, MePEG 2000 60%).

FIG. 14 shows the release of lidocaine (10%) and desoximetasone (1%)from PEG:PLGA:Diblock polymeric paste (50:37:13 w/w %).

FIG. 15 shows the release of lidocaine (8%) from PEG:PLGA pastes (50:50,55:45 and 60:40).

FIG. 16 shows the release of sunitinib (1%) from PEG:PLGA:Diblockpolymeric paste (50:37:13 w/w %).

FIG. 17 shows the release of Tamsulosin (2%) from PEG:PLGA:Diblockpolymeric paste (50:37:13 w/w %).

FIG. 18 shows the release of lidocaine (8%), cephalexin (2%), andibuprofen (5%) from PEG:PLGA:Diblock polymeric paste (50:37:13 w/w %).

FIGS. 19A and 19B show the effect of drug-loaded (i.e. docetaxel (1%),bicalutamide (1%), and VPC-27 (4%)) PEG:PLGA:Diblock polymeric paste(50:37:13 w/w %) versus control paste (i.e. no drug) on mouse serum PSA(FIG. 19A) and absolute tumour size (FIG. 19B) as a representation ofhuman prostate cancer tumors (ST-PC3) in mice. A study to determine theeffect of variable concentrations of docetaxel.

FIGS. 20A and 20B show the effect of varied amounts of Docetaxel (i.e.0%, 0.25%, 0.5% and 1%) drug-loaded (i.e. Bicalutamide (4%), and VPC-27(4%) PEG:PLGA:Diblock polymeric paste (50:37:13 w/w %) on mouse serumPSA (FIG. 20A) and absolute tumour size (FIG. 20B) as a representationof human prostate cancer tumors in mice.

FIGS. 21A and 21B show serum PSA concentrations (FIG. 21A) and tumourvolume in cm³ (FIG. 21B) after intratumoral injection of drug-loadedpastes (1% Docetaxel and 4% Bicalutamide; 1% Docetaxel, 4% Bicalutamideand 4% VPC-27; 1% Docetaxel; and 1% Docetaxel and 4% VPC-27).

FIGS. 22A and 22B show the systemic absorption of lidocaine after localinjection of lidocaine pastes (in PEG/PLGA 50/50) subcutaneously in ratsat different doses of lidocaine paste (i.e. 23 mg/kg; 29 mg/kg; 36mg/kg; 40 mg/kg; and 45 mg/kg) as a measure of serum concentrationobserved over time (FIG. 22A) and as a semi logarithmic plot (FIG. 22B).

FIG. 23 shows the water absorption of pastes containing a swelling agent(i.e. 2% sodium hyaluronate (SH)) and variable amounts of diblockcopolymer (i.e. 10%, 20%, 30% and 40%) as compared to no SH and nodiblock.

FIG. 24 shows the release of 5% Gemcitabine from pastes with (i.e. 2%sodium hyaluronate (SH)) and without swelling agent and with and withoutdiblock copolymer. The pastes had a high PEG300™ content (i.e. 53%, 58%and 76%).

FIGS. 25A and 25B show the urinary excretion after injection of 5%gemcitabine pastes into pig kidney pelvis (FIG. 25A) and serumgemcitabine concentrations after injection of 5% gemcitabine pastes (68%PEG: 30% PLGA) into pig kidney pelvis (FIG. 25B) to show systemicabsorption of gemcitabine paste containing a swelling agent (2% SH) inthree pigs (administration of 1.5 mL of a 5% gemcitabine paste intokidney pelvis using 5F ureteral catheter).

DETAILED DESCRIPTION OF THE INVENTION

In embodiments of the invention hydrophobic water-insoluble polymers areused to control the consistency of biocompatible polymer pastes andsubsequent release of a variety of drugs therefrom.

Inherent Viscosity (IV) is a viscometric method for measuring molecularsize. IV is based on the flow time of a polymer solution through anarrow capillary relative to the flow time of the pure solvent throughthe capillary. The units of IV are typically reported in deciliters pergram (dL/g). IV is simple and inexpensive to obtain and reproducible.Gel Permeation Chromatography (GPC) may be used as a chromatographicmethod for measuring molecular size. The molecular size can be expressedas molecular weight (MW) in Daltons obtained from calibration with astandard polymer (for example, polystyrene standards in chloroform). Themolecular weight of styrene is 104 Daltons and standards of knownpolystyrene are readily available. MWs obtained by GPC are verymethod-dependent and are less reproducible between laboratories.Alternatively, molecular weight may be measured by size exclusionchromatography (SEC), high temperature gel permeation chromatography(HT-GPC) or mass spectrometry (MALDI TOF-MS).

The hydrophobic water-insoluble polymers may be a polyester. Thehydrophobic water-insoluble polymers may be a polylactic-co-glycolicacid (PLGA), wherein, the ratio of LA:GA is equal to or below 75:25. Theratio of LA:GA may be about 50:50. Durect Corporation™ who supplied thePLGA used in these experiments graph inherent viscosity (IV) in dL/g inhexafluoroisopropanol (HFIP) against molecular weight in Daltons fortheir 50:50 and 65:35 LA:GA polymers. Similarly, when Durect™ calculatedthe IV values in dL/g for 75:25 PLGA and 85:15 PLGA, chloroform, wasused as the solvent. The relationship between IV and molecular weight inDaltons is different depending on the ratio of LA:GA. As describedherein an inherent viscosity of between 0.15 to 0.25 dL/g is an optionalrange, but an IV in the range 0.25-0.5 dL/g would also be suitable.Alternatively, the range may be between about 0.15 dL/g and about 0.5dL/g.

Using a 50:50 PLGA a range of 0.15 to 0.25 dL/g is approximatelyequivalent to a range of about 4,300 Daltons to about 6,700 Daltons anda range of 0.25 to 0. 5 dL/g is approximately equivalent to a range ofabout 6,700 Daltons to about 26,600 Daltons. Using a 65:35 PLGA a rangeof 0.15 to 0.25 dL/g is approximately equivalent to a range of about6,500 Daltons to about 14,200 Daltons and a range of 0.25 to 0. 5 dL/gis approximately equivalent to a range of about 14,200 Daltons to about39,000 Daltons. The broader range of 0.15 to 0.5 dL/g is equivalent toabout 4,300 Daltons to about 26,600 daltons for 50:50 PLGA and about6,500 Daltons to about 39,000 daltons for 65:35 PLGA. Accordingly, theDalton range for PLGA may be anywhere between 4,300 and about 39,000.Alternatively, the Dalton range for PLGA may be anywhere between 4,300and about 40,000 or higher if using 75:25 (i.e. up to a molecular weightof 56,500 Dalton). For the 50:50, 65:35 and 75:25 LA:GA polymers, an IVof 0.5 g/dL approximately corresponds to molecular weights of 26,600,39,000, and 56,500. As tested the Durect™ 50:50 having an IV of 0.25dL/g is about 6,700 Daltons, Durect™ 75:25 having an IV of 0.47 dL/g isabout 55,000 Daltons and Durect™ 85:15 having an IV of 0.55 dL/g to 0.75dL/g is in the range of about 76,000 Daltons to about 117,000 Daltons.

Calculations of IV to Dalton's provided by Durect Corporation™ are asfollows (for each ratio of LA:GA). For 50:50 an IV of 0.25 dL/g is about6.700 Daltons, an IV of 0.35 dL/g is about 12,900, Daltons, an IV of0.45 dL/g is about 21,100, an IV of 0.55 dL/g is about 31,100 Daltonsand an IV of 0.65 dL/g is about 43.500 Daltons. For 65:35 an IV of 0.15dL/g is about 6,500 Daltons, an IV of 0.25 dL/g is about 14,200 Daltons,an IV of 0.35 dL/g is about 23,700 Daltons, an IV of 0.45 dL/g is about34,600 Daltons, an IV of 0.55 dL/g is about 47,000 Daltons and an IV of0.65 dL/g is about 60,500 Daltons. For 75:25 an IV of 0.15 dL/g is about11,200 Daltons, an IV of 0.25/0.3 dL/g is about 23,800 Daltons, an IV of0.35/0.4 dL/g is about 39,000 Daltons, an IV of 0.45/0.5 dL/g is about56,500 Daltons and an IV of 0.55/0.6 dL/g is about 76,000 Daltons.

Of particular interest are PLGA pastes having a ratio of LA:GA of 50:50with an IV of between 0.15 dL/g to 0.25 dL/g (i.e. molecular weights ofbetween 4,300 Daltons to 6,700 Daltons). However, PLGA pastes having aratio of LA:GA of 50:50 with an IV of 0.25 dL/g to 0.5 dL/g (i.e. amolecular weight of about 6,700 to about 26,600 Daltons) is also useful.

The PLGA polymer molecular weight may be reported as inherent viscosity(IV)) may be IV=0.15-0.5 dL/g. The PLGA polymer IV may be <0.3 dL/g. ThePLGA polymer density may lie between 0.15-0.25 dL/g. Low molecularweight versions of PLGA with a 50:50 ratio of LA:GA and an inherentviscosity under 0.3 dL/g may be rendered fully miscible with a lowmolecular weight biocompatible glycol using mild heating to form eithera viscous or fluid paste at room temperature. For high viscosity pastes,the 50:50 ratio PLGA materials with an inherent viscosity up to 0.5 dL/gmay be used with poly ethylene glycol (PEG). PEG or mePEG with amolecular weight below 1450 may be used in these applications. The lowmolecular weight biocompatible glycol may have a molecular weightbetween about 76 and about 1450. The PEG or mePEG may have an averagemolecular weight of between 300 and 1450.

Low molecular weight biocompatible glycol may be used to fluidize PLGAto a paste and set to an implant. Examples of a low molecular weightbiocompatible glycol may include PEG, mePEG and propylene glycol. APEG-based glycol (i.e. mePEG or PEG) may have a molecular weight of upto 1450. Alternatively, the PEG-based excipient may have a molecularweight 900. In a further alternative, a PEG-based excipient may have amolecular weight of about 300. PEG300™ is biocompatible and is directlycleared via the kidneys without liver or other degradation required.

PLGA:PEG pastes may be loaded with a variety of drugs and allow forcontrolled release of the loaded drug(s) over periods of approximately1-2 months. Low molecular weight diblock copolymers may also beoptionally incorporated without phase separation into the PLGA:PEGcompositions with only minor changes in viscosity of the totalcomposition. The presence of diblock copolymers may allow furthercontrol (acceleration) of drug release from the polymer matrix so thatcertain drugs that release slowly may be released more rapidly.

Diblock copolymers may consist of two different types of monomers. Themonomers may be hydrophobic. The monomers may be hydrophilic. Thediblock copolymer may have one hydrophobic monomer and one hydrophilicmonomer. The diblock copolymer may be amphiphilic. The hydrophilicmonomer for example, may be PEG or MePEG. The hydrophobic monomer forexample, may be PLGA, PLA, PLLA or PCL. TABLE 1 below provides a rangeof compositions that were made and tested to determine theircharacteristics and useful features.

TABLE 1 provides examples of various polymer formulations as tested.Optional Injectability Set time PLGA IV or Diblock Form at (needle inwater alternative % Glycol % Copolymer % injection size/force) starts0.15-0.25 25 PEG 300 ™ 75 Fluid paste 23 gauge/easy 1 minute 0.15-0.2537 PEG 300 ™ 63 paste 22 gauge/easy 1 minute 0.15-0.25 50 PEG 300 ™ 50paste 22 1 minute gauge/moderate 0.15-0.25 24 PEG 300 ™ 50 Diblock 26paste 22 1-2 gauge/moderate minutes 0.15-0.25 37 PEG 300 ™ 50 Diblock 13paste 22 gauge/easy- 1-2 moderate minutes 0.15-0.25 40 PEG 750 ™ 60paste 22 gauge/ 1-2 moderate minutes 0.15-0.25 40 PEG 900 ™ 60 paste 223-5 gauge/difficult minutes 0.15-0.25 30 PEG 1450 ™ 70 Wax/paste 16 1minute gauge/difficult/ needs 37° C. 0.15-0.25 40 MethoxyPEG 60 paste 22gauge/ 1-2 750 moderate minutes 0.15-0.25 50 Propylene 50 Very viscous16 gauge/difficult 1 hour Glycol paste 0.25-0.50 35 PEG 300 ™ 65 Medium18 gauge/e 5 viscous 16 gauge/easy minutes paste 0.47-0.55* 50 PEG 300 ™50 Very viscous 16 1 hour paste gauge/difficult 0.47-0.55* 40 PEG 300 ™60 viscous 16 gauge 0.5-1 paste easy hour 0.47-0.55* 30 PEG 300 ™ 70paste 16 gauge 3-5 min easy 0.47-0.55* 20 PEG 300 ™ 80 liquid paste 16gauge/very 1 easy minute, but dissolves away More viscous injectables(needs pressure for injection - waxy prior to injection, delayed settime) 0.25-0.50 35 Propylene 65 Almost 16 1-2 hour glycol solid/pastegauge/extreme force 0.15-0.25 50 Pluronic 50 Very viscous 16 1 hourL101 ™ paste gauge/difficult PLLA 2K 40 PEG 300 ™ 60 Wax 16 5gauge/extreme minutes PCLdiol 60 PEG 300 ™ 40 Wax 18 2 1250gauge/difficult minutes sets to v hard implant Not injectable usingnormal gauge needles or a reasonable amount of force 0.55-0.75 20 PEG300 ™ 80 No Not injectable n/a homogenous paste 0.55-0.75 30 PEG 300 ™70 No Not injectable n/a homogenous paste 0.55-0.75 40 PEG 300 ™ 60 NoNot injectable n/a homogenous paste 0.55-0.75 50 PEG 300 ™ 50 No Notinjectable n/a homogenous paste *the PLGA was not from Durect ™ and theIV values for these PLGAs were estimated based on the ratio of LA:GA of75:25.

Drug delivery compositions described herein may exist in a variety of“paste” forms. Examples of paste forms may include liquid paste, pasteor wax-like paste, depending on to polymers used, the amount of thepolymers used and the temperature.

Drug delivery compositions described herein may release one or moredrugs over a period of several hours or over several months, dependingon the need. Compositions described herein may be used for localizeddelivery of one or more drugs to a subject. Examples of drugs that maybe delivered using these compositions are not limited, and may includeanti-cancer drugs, anti-inflammatory agents, anti-bacterial,anti-fibrotic, analgesic. Examples of anti-cancer drugs that may be usedwith the compositions of the present invention include docetaxel,paclitaxel, mitomycin, cisplatin, etoposide vinca drugs, doxorubicindrugs, rapamycin, camptothecins, gemcitabine, finasteride (or othercytotoxics); bicalutamide, enzalutamide, VPC-27, tamoxifen, sunitinib,erlotinib. Anti-cancer biological agents may also be used in theformulation such as antibody based therapies e.g. Herceptin, Avastin,Erbitux or radiolabelled antibodies or targeted radiotherapies such asPSMA-radioligands. Anti-inflammatory agents may include non-steroidaldrugs like ibuprofen, steroids like prednisone. Local analgesia or localanesthetic medications may include, for example, one or more of thefollowing: Procaine; Benzocaine; Chloroprocaine; Cocaine;Cyclomethycaine; Dimethocaine/Larocaine; Piperocaine; Propoxycaine;Procaine/Novocaine; Proparacaine; Tetracaine/Amethocaine, Articaine;Bupivacaine; Cinchocaine/Dibucaine; Etidocaine; Levobupivacaine;Lidocaine/Lignocaine/Xylocaine; Mepivacaine; Prilocaine; Ropivacaine;and Trimecaine. Antibiotic medications may include penicillin,cephalexin, gentamicin, ciprofloxacin, clindamycin, macrodantin, andothers. The drugs may be hydrophobic or may be hydrophilic. Specificdrugs may be selected from one of more of the following: Docetaxel;VPC-27; Bicalutamide; Cephalexin (A); Sunitinib; Tamsulosin;Desoximetasone; Gemcitabine; Rapamycin; and Ibuprofen.

Hydrophobic drugs may be able to bind with strong affinity to thehydrophobic water-insoluble polymer (ex. PLGA) allowing slowdissociation and controlled release from the implant. Such drugs tend todissolve (at least partially) in the paste mixture. Hydrophilic drugsmay be blended into the paste but because the matrix is partiallyhydrated in aqueous environments, these drugs may dissolve out of theimplant quickly. In some situations this may be desirable, such as whenan antibacterial drug may be included in the paste to treat a localinfection and it is preferred if all the drug is cleared form the pastein 7 days to suit an antibacterial drug treatment regime.

Drug delivery compositions may be prepared and utilized to treat orprevent a variety of diseases or conditions. Examples of diseases orconditions that may be treated, may for example, include cancer, pain,inflammatory conditions, fibrotic conditions, benign tumors (includingbenign prostate hyperplasia), and infections.

Local anesthetics usually fall into one of two classes: aminoamide andaminoester. Most local anesthetics have the suffix “-caine”. The localanesthetics in the aminoester group may be selected from one or more ofthe following: Procaine; Benzocaine; Chloroprocaine; Cocaine;Cyclomethycaine; Dimethocaine/Larocaine; Piperocaine; Propoxycaine;Procaine/Novocaine; Proparacaine and Tetracaine/Amethocaine. The localanesthetics in the aminoamide group may be selected from one or more ofthe following: Articaine; Bupivacaine; Cinchocaine/Dibucaine;Etidocaine; Levobupivacaine; Lidocaine/Lignocaine/Xylocaine;Mepivacaine; Prilocaine; Ropivacaine; and Trimecaine. Local anestheticsmay also be combined (for example, Lidocaine/prilocaine orLidocaine/tetracaine).

Furthermore, local anesthetics used for injection may be mixed withvasoconstrictors to increase residence time, and the maximum doses oflocal anesthetics may be higher when used in combination with avasoconstrictor (for example, prilocaine hydrochloride and epinephrine;lidocaine, bupivacaine, and epinephrine; lidocaine and epinephrine; orarticaine and epinephrine).

Anti-cancer drugs as may be used in the composition described herein,may be categorized as alkylating agents (bi and mono-functional),anthracyclines, cytoskeletal disruptors, epothilone, topoisomeraseinhibitors (I and II), kinase inhibitors, nucleotide analogs andprecursor analogs, peptide antibiotics, platinum-based agents, vinkaalkaloids, and retinoids. Alkylating agents, may be bifunctionalalkylators (for example, Cyclophosphamide, Mechlorethamine, Chlorambuciland Melphalan) or monofunctional alkylators (for example, Dacarbazine(DTIC), Nitrosoureas and Temozolomide). Examples of anthracyclines areDaunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, andValrubicin. Cytoskeletal disruptors or taxanes are Paclitaxel,Docetaxel, Abraxane and Taxotere. Epothilones may be epothilone orrelated analogs. Histone deacetylase inhibitors may be Vorinostat orRomidepsin. Inhibitors of topoisomerase I may include Irinotecan andTopotecan. Inhibitors of topoisomerase II may include Etoposide,Teniposide or Tafluposide. Kinase inhibitors may be selected fromBortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib or Vismodegib.Nucleotide analogs and precursor analogs may be selected fromAzacitidine, Azathioprine, Capecitabine, Cytarabine, Doxifluridine,Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate orTioguanine/Thioguanine. Peptide antibiotics like Bleomycin orActinomycin. Platinum-based agents may be selected from Carboplatin,Cisplatin or Oxaliplatin. Retinoids may be Tretinoin, Alitretinoin orBexarotene. The Vinca alkaloids and derivatives may be selected fromVinblastine, Vincristine, Vindesine and Vinorelbine.

An anti-cancer drug that may be used with the compositions describedherein, may be selected from one or more of: Actinomycin; All-transretinoic acid; Azacitidine; Azathioprine; Bleomycin; Bortezomib;Carboplatin; Capecitabine; Cisplatin; Chlorambucil; Cyclophosphamide;Cytarabine; Daunorubicin; Docetaxel; Doxifluridine; Doxorubicin;Epirubicin; Epothilone; Etoposide; Fluorouracil; Gemcitabine;Hydroxyurea; Idarubicin; Imatinib; Irinotecan; Mechlorethamine;Mercaptopurine; Methotrexate; Mitoxantrone; Oxaliplatin; Paclitaxel;Pemetrexed; Teniposide; Tioguanine; Topotecan; Valrubicin; Vemurafenib;Vinblastine; Vincristine; Vindesine; and Vinorelbine. Alternatively, theanti-cancer drug may be a biological agent and may be selected fromHerceptin (Trastuzumab), Ado-trastuzumab, Lapatinib, Neratinib,Pertuzumab, Avastin, Erbitux or radiolabelled antibodies or targetedradiotherapies such as PSMA-radioligands. The anti-cancer drug may be anAndrogen Receptor, an Estrogen Receptor, epidermal growth factorreceptor (EGFR) antagonists, or tyrosine kinase inhibitor (TKI). Ananti-angiogenesis agent may be selected from avastin, an epidermalgrowth factor receptor (EGFR) antagonists or tyrosine kinase inhibitor(TKI). An Immune modulator such as Bacillus Calmette-Guerin (BCG).

As used herein a “drug” refers to any therapeutic moiety, which includessmall molecules and biological agents (for example, proteins, peptides,nucleic acids). Furthermore, a biological agent is meant to includeantibodies and antigens. As used herein, the term drug may in certainembodiments include any therapeutic moiety, or a subset of therapeuticmoieties. For example, but not limited to one or more of the potentiallyoverlapping subsets and one or more drugs, as follows: hydrophobicdrugs, hydrophilic drugs; a cancer therapeutic drug; a local anestheticdrug; an anti-biotic drug; an anti-viral drug; an anti-inflammatorydrug; a pain drug; an anti-fibrotic drug; or any drug that might benefitfrom a localized and/or sustained release.

As used herein, “an antibody” is a polypeptide belonging to theimmunoglobulin superfamily. In particular, “an antibody” includes animmunoglobulin molecule or an immunologically active fragment of animmunoglobulin molecule (i.e., a molecule(s) that contains an antigenbinding site), an immunoglobulin heavy chain (alpha (α), mu (μ), delta(δ) or epsilon (ε)) or a variable domain thereof (VH domain), animmunoglobulin light chain (kappa (κ) or lambda (λ)) or a variabledomain thereof (VL domain), or a polynucleotide encoding animmunoglobulin molecule or an immunologically active fragment of theimmunoglobulin molecule. Antibodies includes a single chain antibody(e.g., an immunoglobulin light chain or an immunoglobulin heavy chain),a single-domain antibody, an antibody variable fragment (Fv), asingle-chain variable fragment (scFv), an scFv-zipper, an scFv-Fc, adisulfide-linked Fv (sdFv), a Fab fragment (e.g., CLVL or CHVH), aF(ab′) fragment, monoclonal antibodies, polyclonal antibodies. As usedherein “antigen” refers to any epitope-binding fragment and apolynucleotide (DNA or RNA) encoding any of the above.

As used herein, a “paste” is any composition described herein that hasthe characteristics of a solid and of a liquid depending on applied loadand the temperature. Specifically, the viscosity of a paste may beanywhere in the range of about 0.1 to about 200 pascal seconds (Pa·s) atroom temperature and may be measured by any number of methods known tothose of skill in the art. Numerous types of viscometers and rheometersare known in the art. For example, a cone and plate rheometer (i.e.Anton Paar™, MCR 502).

As used herein a “swelling agent” is meant to encompass anybiocompatible agent that will increase the volume of a paste asdescribed herein, once the paste with swelling agent incorporated isplaced in an aqueous environment. A swelling agent may be selected from:salts of hyaluronic acid (e.g., sodium hyaluronate); cellulosederivatives (e.g., carboxymethylcellulose); or polyacrylic acidderivatives (e.g., Carbomers). A swelling agent may advantageously beapproved for use in injectable compositions. Also having a swellingagent that does not interfere with the injectability of the paste (forexample, is not too grainy, does not precipitate and is easy to disperseagain) would be of benefit. It may also be advantageous, if the swellingagent is able to provide a suitable amount of swelling without reducingthe overall % of the polymers of the paste as described herein (i.e. bea small percentage of the overall paste). Furthermore, a swelling agentthat exhibits high rate of swelling and quick swelling characteristics(for example, swell within minutes of injection) would be beneficial.

Methods Paste Preparation

The paste was prepared by weighing the polymers into a glass vial andstirring at 60° C. The polymers formed a homogenous melt. If drug is tobe added, it is added following the polymer paste preparation. Thevalues for the paste polymers (i.e. hydrophobic water-insoluble polymer;low molecular weight biocompatible glycol; and, if used, the di-blockcopolymer and/or swelling) is prepared as a total % out of 100% beforemixing with drug. When the drug is added the % associated therewith is apercent of the total composition with drug and the “pre-drug paste”component % s are based on their proportions prior to adding the drug.For example, 4% means 4 g of drug in 100 g paste. Drug(s) wereincorporated using levigation or a mortar and pestle.

The injectability of a paste will depend on many parameters (i.e. needlesize, needle lengths, volume, tissue backpressure, strength of theperson administering the paste). Normally it is preferred that a pastebe easily drawn up into a syringe using a 14 gauge needle and easilyinjected into a tissue zone using an 18 gauge or even smaller needlewith a small amount of extra pressure. However, for particular uses anddepending on the gauge of the needle, having a more viscous paste (i.e.more difficult to inject), may be desirable.

Viscosity Measurement

Viscosity measurements were taken using a cone plate rheometer (AntonPaar™, MCR 502) and recorded as a function of shear rate at constanttemperature.

Water Absorption by Pastes Containing a Swelling Agent

Pastes containing a swelling agent were prepared by incorporatingincreasing amounts of a base paste (PEG:PLGA) into the swelling agent(sodium hyaluronate) using mortar and pestle. Around 20 mg of pastesamples (n=3) for each paste formulation were weighed on filtermembranes (0.45 μm) and repeatedly weighed after soaking in water at 37°C. For each time point, excess water was carefully removed using avacuum pump.

In Vitro Drug Release Assays

The drug-loaded paste can be aliquoted for in vitro release studies.Paste (50-100 mg) is deposited at the bottom of a test tube and releasemedium is added (5-10 mL, sink conditions). Release medium is phosphatebuffered saline (PBS, 10 mM, pH 7.4)) or PBS containing 1% Albumin. Thetest tubes are kept in a 37° C. incubator until the end of the study.Release samples are taken at appropriate time points by replacing thecomplete release medium (supernatant) and analyzing it for total drugusing Reversed phase high-performance liquid chromatography withultraviolet (UV) detection (RP-HPLC-UV).

TABLE 1 Chromatographic parameters used in RP-HPLC ParameterSpecification HPLC Waters (1525 Binary HPLC Pump, 2489 UV/VisibleDetector, 717 plus Autosampler) Detector UV/Visible Flow rate 1 mL/minColumn C-18, Nova-Pak, 4 μm, 3.9 × 150 mm Column Temperature Ambient, notemperature control Injection Volume 20 μL Elution isocratic

TABLE 2 Mobile phase, retention times and UV detection wavelength forstudied drugs. Retention UV detection Mobile phase composition timewavelength Drug (v/v) (min) (nm) Bicalutamide/ 30/30/40 3 min 272enzalutamide Acetonitrile/methanol/water (adjusted to pH 3.4 withglacial acetic acid) Docetaxel 30/30/40 6 min 228Acetonitrile/methanol/water (adjusted to pH 3.4 with glacial aceticacid) VPC-27 300/180/35 4.3 min 244 Acetonitrile/methanol/water + 200 μLglacial acetic acid Rapamycin 200/175/125 2.9 min 278Acetonitrile/methanol/water Cephalexin 20/80 5 min 254Acetonitrile/water (adjusted to pH 3.4 with glacial acetic acid)Lidocaine 50/50 3.2 min 220 Acetonitrile/ammoniumacetate 20 mM (pH 6.4)Desoximetasone 50/50 2 min 244 Acetonitrile/ammoniumacetate 20 mM (pH6.4) Sunitinib 55/45 4 min 431 Acetonitrile/ammoniumacetate 20 mM (pH6.4) Tamsulosin 50/50 2.3 min 220 Acetonitrile/ammoniumacetate 20 mM (pH6.4) Ibuprofen 50/50 1.9 min 220 Acetonitrile/ammoniumacetate 20 mM (pH6.4) Gemcitabine 3/97 2.3 min 272 methanol/water (adjusted to pH 3.4with glacial acetic acid)

Intratumoral Paste Injection

Athymic male nu/nu mice (uncastrated) have been injected with 4×10⁶LNCap cells suspended in Matrigel™ subcutaneously in the left flank.Treatment allocation began once a single site tumor reached 150-200 mm³via caliper measurement. Drug-loaded paste (30 μL) was injected into thetumor using a 21 gauge needle. Serum prostate specific antigen (PSA)levels were measured over time and tumor size was monitored.

In another experiment, groups of five to six animals received 30-40 μLpaste intratumorally once the tumor had reached a size of 100 mm³. Tumorgrowth and serum PSA levels were monitored for the following 12 weeks.Local delivery of paste subcutaneously in rats.

Five groups of rats (male, Sprague Dawley™) with six animals in eachgroup received one injection of paste formulation (0.1 mL)subcutaneously in their flank. The paste formulation was based on a50:50 mixture of PEG300™ and PLGA. Lidocaine was incorporated into thepaste at 80, 100, 120, 140, and 160 mg per g of paste. The correspondingdoses for each group were 23, 29, 36, 40 and 45 mg of Lidocaine per kg.

Blood was collected from the saphenous vein over four weeks at 0, 0.25,1, 4, 24, 48, 168 336, 504 and 672 hours after injection. Lidocaineconcentrations in rat serum were determined using ultra high performanceliquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Anon-compartmental analysis was then applied to each data set usingPhoenix 64™ (Build 6.3.0.395) WinNonlin 6.3™ to determine relevantpharmacokinetic parameters.

Kidney Pelvis Injection of Paste

After placement of a ureteral catheter, three pigs received an injectionof 1-2 mL of polymeric paste into the kidney pelvis. After removal ofthe ureteral catheter, a urinary catheter was placed and urine collectedfor 3 h intervals over 24 h. Blood was collected from an ear vein over24 h and gemcitabine concentrations were determined using ultra highperformance liquid chromatography tandem mass spectrometry(UHPLC-MS/MS).

EXAMPLES Example 1. Viscosity of Polymeric Pastes Manufactured UsingDifferent Ratios of PLGA, PEG and Diblock Copolymer

The polymeric paste is a biocompatible formulation comprised of two orthree constituents: poly-(lactic-co-glycolic) acid (PLGA), a diblockcopolymer of DL-lactide (DLLA) (optional) and methoxy polyethyleneglycol (mePEG) termed poly(DL-lactide)-methoxy polyethylene glycol(PDLLA-mePEG), and polyethylene glycol with a molecular weight of 300 Da(PEG 300™). Drug or drug mixtures can be incorporated into the pastethrough levigation with a spatula and the paste can be injected througha 20 G needle. The PLGA is comprised of equal amounts of LA and GA(50:50 Poly[DL-lactide-co-glycolide]) and may have a degradation time of1-2 months. The polymeric drug delivery paste may be an injectableviscous solution at 37° C. After injection into an aqueous tissueenvironment, the paste may transform into a waxy solid, which may serveas a sustained release platform for incorporated drug(s).

Polymeric pastes were manufactured using different weight ratios of PLGA(Durect™, Alabama) (IV=0.15-0.25 dL/g, 50:50 ratio of LA to GA), PEGwith a molecular weight of 300 Da (Polysciences™, USA) and diblockcopolymer (synthesized in house, MW=3333 Da, comprising 40% PLLA and 60%methoxypolyethylene glycol (w:w)). The diblock copolymer may be used toadjust the degradation profile of the polymeric paste and the releaseprofile of the drug(s). The diblock copolymer can help to encapsulatehydrophobic drugs due to its amphiphilic characteristics. In aqueoussolution, the diblock can spontaneously arrange itself in micelles thatcan host hydrophobic drug in the poly (DL lactic acid) (PDLLA) coresurrounded by the hydrophilic PEG or mePEG chains⁵³⁻⁵⁵.

The components were weighed into a glass vial and stirred overnight at37° C. to form a homogenous mixture. Viscosity measurements were takenusing a cone plate rheometer (Anton Paar™, MCR 502) and recorded as ashear rate at constant temperature. Pastes comprised of PEG and PLGA hadvery low viscosities at low PLGA content such that the viscosity ofpastes at 80% PEG were less than 1 Pa·s. FIG. 1 shows that as theconcentration of PLGA increased, paste viscosity rose very quickly toover 100 Pa s for the 40% PEG and 60% PLGA composition. FIG. 1 alsoshows that the addition of diblock copolymer in place of PLGA reducedthe viscosity considerably so that at 13% diblock with 50% PEG and 37%PLGA the viscosity was less than 10 Pas, and was reduced even furtherusing 26% diblock.

Example 2. The Release of PEG300™ from Polymeric Paste

Seven compositions of polymeric pastes were manufactured from PLGA, PEGand diblock copolymer as described in EXAMPLE 1. For each of the sevendifferent polymeric pastes, 8×100 mg each were weighed into the cornerof 8×20 ml pre-weighed scintillation vials by holding each vial at aslight angle. 10 ml of water was added to each vial with the vial stillheld at an angle so the paste remained in the vial corner whilst exposedto water. After 10 minutes the outer surface of each paste whitenedslightly indicating setting of the paste and the vials were thenreoriented to the vertical position. This procedure prevented apremature disruption of the setting paste upon exposure to waterturbulences. The vials were capped and placed in a 37° C. oven. Atvarious time points the vials were removed, water was aspirated and thecontents dried for one hour in a 37° C. incubator followed by one day ofvacuum drying at room temperature. The vials were then re-weighed todetermine the weight loss of water-soluble polymer (PEG or diblock) thatdissolved into the water from the polymer paste. FIG. 2 shows that mostof the PEG or diblock was released by 2 days. The values of % polymerreleased approximately matched the initial weight of PEG and diblockpresent by % in each formulation.

Example 3. Release of Docetaxel, VPC-27 and Bicalutamide from PolymericPastes

Polymeric pastes were manufactured from 50:50, 55:45, 60:40 weight ratiocompositions of PLGA (50:50 IV=0.15-0.25 dL/g) and PEG300™, 50:37:13ratios of PEG:PLGA:Diblock, or 50:24:26 ratios of PEG:PLGA:Diblock usingthe methods described in EXAMPLE 1. The presence of the diblockcopolymer allows more detailed control of drug release. This diblockcopolymer has been previously described to increase the water solubilityof hydrophobic drugs by forming diblock micelles with hydrophobic coresthat allows the drugs to partition into the core and increase theapparent solubility. In the paste application as water enters the pastematrix the water soluble diblock begins to dissolve out and any drugdispersed at the molecular level may become “micellized” in the diblockmilieu to increase drug release. The drugs VPC-27, bicalutamide ordocetaxel were added at various weight ratios directly into the pastewith mixing by standard spatula levigation techniques. The drug releasewas studied according to the descriptions found in the general methodssection (In vitro drug release assays, TABLE 1 and TABLE 2).

FIGS. 3A and 3B show the release of VPC-27, docetaxel and bicalutamidefrom a 50:50 (PEG:PLGA) paste. Docetaxel (at 4% w/w) and bicalutamide(at 4% w/w) released with similar profiles showing a fast burst ofrelease over 5 days (10% drug released) followed by a slower moresustained release over the next 40 days where a further 20% ofencapsulated drug was released (FIG. 3A). VPC-27 (at 10% w/w) releasedslowly from the paste reaching about 15% of total encapsulated drugreleased by day 45 (FIG. 3A). When the concentration of VPC-27 wasreduced to 4%, the release profiles of docetaxel and bicalutamide weresimilar to each other but a little slower overall than from the pastecontaining 10% VPC-27. However, the release rate of VPC-27 was almostthe same as the other two drugs using a 4% w/w drug loading (FIG. 3B).

FIGS. 4A to 4C show the release of docetaxel, Bicalutamide, and VPC-27from PEG:PLGA:Diblock pastes 50:37:13 w/w % or 50:24:26 w/w %. FIG. 4Ashows that the release rate of docetaxel from 13% and 26% diblock loadedpastes is increased in comparison to the 50:50 paste mixtures shown inFIGS. 3A and 3B (no diblock). FIG. 4A further shows that by day 10,between 40 and 60% of encapsulated docetaxel was released from the 13%and 26% diblock pastes as compared to less than 17% being released fromthe 50:50 pastes shown in FIGS. 3A and 3B. The addition of diblockcopolymer to the PEG:PLGA paste had a similar effect on the releaserates of bicalutamide (FIG. 4B) and VPC-27 (FIG. 4C). By day 10, therelease was approximately 60% for both drugs at a diblock loading of13%, and approximately 100% for pastes containing 26% diblock comparedto less than 17% release for either drug from 50:50 pastes with nodiblock.

FIG. 5 shows the release of docetaxel (0.25%), bicalutamide (4%), andVPC-27 (4%) w/w) from a PEG:PLGA:Diblock paste (50:37:13 w/w %). Drugrelease was characterized by a small burst release within the first dayand a slower release of drug over the next 35 days. After one day, 24%docetaxel, 8% bicalutamide and 12% VPC-27 were released, followed by aslow release reaching 32% docetaxel, 16% bicalutamide and 19% VPC-27, onday 35 (FIG. 5).

FIGS. 6A to 6D show the effect of varying PLGA:Diblock ratios on therelease rates of docetaxel (0.5%), bicalutamide (4%) and VPC-27 (4%)from PEG:PLGA:Diblock pastes (50:Y:X w/w %). Diblock (X) varied from 7,13, 19 to 25% and PLGA (Y) varied accordingly from 43, 37, 31 to 25% w/w%.

FIGS. 6A to 6D show that by increasing diblock paste content (7%, 13%,19%, 25%) and decreasing PLGA content, drug release rates increased. Forexample, at the low diblock concentration, docetaxel was released in aburst of 20% on day 1 and reached 34% on day 21 (FIG. 6A); while at thehigh diblock concentration, docetaxel was released in a burst of 67% onday 1 and reached 78% on day 21 (FIG. 6D). The effect was similarlypronounced for bicalutamide and more pronounced for VPC-27 (FIGS. 6A to6D).

FIGS. 7A to 7C show how high amounts of PEG affects the release rates ofdocetaxel (4%), bicalutamide (4%) and VPC-27 (4%) from PEG:PLGA pastes(63:37 or 76:24). At too high a ratio of PEG to PLGA the paste may bevery fluid and tends to disintegrate in vivo because the PLGA is overdispersed and unable to form a cohesive solid. Docetaxel releasedquickly from the high PEG content pastes reaching between 40% and 50%released drug at day 11 (FIG. 7A). Neither bicalutamide nor VPC-27released quickly from either of the high PEG pastes, but release wassteady and continuous even after 28 days (FIGS. 7B and 7C). At 11 days,drug release from either high PEG paste formulation was below 22% forboth bicalutamide and VPC-27.

FIGS. 8A to 8C show more release profiles of docetaxel (1%),bicalutamide (4%), and VPC-27 (4%) from PEG:PLGA pastes without diblock.Three pastes were prepared with 50:50, 55:45, 60:40 PEG:PLGA (w/w %).The pastes stayed cohesive and the release of the drugs increased withincreasing PEG content. The release of the three drugs in the 50:50paste was around 2-5%, for the 55:45 paste around 10% and for the 60:40paste between 10 and 20% on day 18.

Example 4. Release of Rapamycin from Polymeric Pastes

Polymeric pastes comprised of 50% PEG300, 37% PLGA (IV 0.15, 50:50ratio) and 13% diblock copolymer containing a drug mixture of docetaxel,rapamycin and VPC-27 (at 1%, 1% and 4% w/w, respectively) weremanufactured as described in the general methods section. Drug releaseexperiments were performed as described previously (In vitro drugrelease assays, TABLE 1 and TABLE 2).

FIG. 9 shows the release rates for docetaxel, rapamycin, and VPC-27,from PEG:PLGA:Diblock pastes (50:37:13). Docetaxel released in asustained manner reaching almost 45% drug release at day 8. VPC-27released well, reaching almost 20% release at day 8. Rapamycin releasedvery slowly with only 4% of the encapsulated drug being released at day8.

Example 5. Release of Cephalexin from Polymeric Paste

Polymeric pastes comprised of 50% PEG300, 37% PLGA (IV 0.15, 50:50ratio) and 13% diblock copolymer containing cephalexin at between 2 and19% loading were prepared as described in Examples 1 and 3. Forcephalexin, albumin was not included in the PBS as this drug is watersoluble. The drug release was studied according to the descriptionsfound in the general methods section (In vitro drug release assays,TABLE 1 and TABLE 2). FIGS. 10A and 10B show that Cephalexin releasedquickly from the polymeric pastes where almost all drug was releasedfrom drug loaded pastes at 1 day.

Example 6. Effect of Paste Geometry and Drug Loading on the Release ofLidocaine from Polymeric Paste

PEG:PLGA:Diblock paste (50:37:13) containing lidocaine (non-HCl form) at2-10% w/w loading were mixed as previously described. To achievedifferent paste geometries, the 8% w/w paste was placed in a syringe and100 mg samples were extruded through an 18 gauge needle onto the base ofa cold (approximately 2° C.) 20 ml glass scintillation vial as either acylinder, a crescent shape in the lower corner of a tilted vial or as ahemisphere “blob” in the middle of the base of the vial. The coldtemperature assisted in keeping the shape of the very viscous paste atthis temperature. 10 ml of cold PBS were very gently added and the vialwas left for 10 minutes to allow the outer surface of the paste towhiten a little. The vials were then placed in a 37° C. incubator. Atdedicated time points the 10 ml of PBS were removed and replaced withanother 10 ml of room temperature PBS. The drug release was studiedaccording to the descriptions found in the general methods section (Invitro drug release assays, TABLE 1 and TABLE 2).

Lidocaine released from all geometric forms with a burst phase betweenapproximately 50% and 70% at day 2 (FIG. 11A). After that the releaserate slowed, especially for the hemisphere shape, such that by day 7this shape had released approximately 65% of the drug as compared to 88%and 92% released from the crescent and cylinder shapes, respectively.All paste shapes released small amounts of lidocaine between 7 to 28days. The release rates for lidocaine using different % w/w loadingswere similar and are shown in FIG. 11B.

Example 7. Release of Docetaxel, VPC-27 and Enzalutamide from PolymericPastes

Polymeric pastes were manufactured from 63:37 compositions of PEG300™and PLGA (50:50 IV=0.15) or from 50:37:13 ratios of PEG:PLGA:Diblockusing the method described earlier. The drugs VPC-27, enzalutamide ordocetaxel were added at various weight ratios directly into the pastewith mixing by standard spatula levigation techniques. The drug releasewas studied according to the descriptions found in the general methodssection (In vitro drug release assays, TABLE 1 and TABLE 2). All drugsreleased more quickly from the diblock containing paste than the highPEG content paste as shown in FIGS. 12A to 12C. From the high PEGcontent PEG:PLGA paste (63:37), VPC-27 released slowly without anyapparent burst phase of release (FIG. 12C) but a burst phase occurredfrom the PEG:PLGA:diblock containing paste (50:37:13), resulting innearly 35% of drug released by day 50 (FIG. 12C). Docetaxel releasedwell from both pastes (approximately 50% released by day 50) (FIG. 12A)and enzalutamide released approximately 40% of the total encapsulateddrug by day 50 (FIG. 12B).

Example 8. Solubilization of Drugs by Diblock Copolymer

Diblock copolymer (molecular weight 3333, PLLA 40%, MePEG 2000 60%) wasweighed out into 2 ml glass vials in various amounts at concentrationsof 0 to 45 mg/ml. The drugs docetaxel, bicalutamide, and VPC-27 wereadded in a drug polymer ratio of 1:9 (one part drug, 9 parts diblockcopolymer) from stock solutions in acetonitrile and topped up toapproximately 1 ml. All contents were in solution and the vials weredried down under nitrogen with mild heat followed by vacuum overnight.The vials were then warmed to 37° C. and 1 ml of PBS at 37° C. wasadded. The vials were vortexed to dissolve their contents and thecontents were then centrifuged at 15000 rpm in a microfuge and filteredthrough a 0.2 μm filter to give a clear solution. The concentration ofeach drug in each solution was then measured using RP-HPLC described inthe general methods section (In vitro drug release assays, TABLE 1 andTABLE 2). Drugs were solubilized effectively by the diblock copolymer asshown in FIG. 13. For VPC-27 and docetaxel, drug concentrations in the3.5 to 5 mg/ml range were achieved. Above a diblock concentration of 20mg/ml, bicalutamide did not stay in solution as shown in FIG. 13.

Example 9. Release of Lidocaine (10%) and Desoximetasone (1%) fromPEG:PLGA:Diblock Paste (50:37:13)

The paste was manufactured as in EXAMPLE 7 using lidocaine at 10% anddesoximetasone at 1%. Drug release was measured using RP-HPLC asdescribed earlier (In vitro drug release assays, TABLE 1 and TABLE 2).

FIG. 14 shows that lidocaine released in the same manner as previouslyobserved with a 50% burst within the first day and an extended releasereaching 80% by day 35. Similarly, desoximetasone released with a burstof 50% on day one and reached 100% release on day 35. The injectablelidocaine pastes keep the drug near the local injection site and delayssystemic uptake of lidocaine. The suggested drug load is 10% and themaximum injectable volume should be 3 g of paste into the spermatic cordto stay below the maximum single dose of 300 mg. Lidocaine is releasedin a sustained fashion while the paste degrades.

Example 10. Release of Lidocaine from Various PEG:PLGA Pastes withoutDiblock

Pastes were manufactured as described in EXAMPLE 1. FIG. 15 shows thelidocaine release from PEG:PLGA pastes without diblock. Three pasteswere prepared with 50:50, 55:45, 60:40 PEG:PLGA (w/w %) and 8% lidocaine(w/w). The pastes stayed cohesive and drug release was faster in pasteswith higher PEG content. Lower PEG content decreased the amount of burstrelease slightly and by day 18, 100% of lidocaine was released from allpastes.

Example 11. Release of Sunitinib from PEG:PLGA:Diblock Polymeric Paste(50:37:13)

The paste was manufactured as in EXAMPLE 7 and the drug Sunitinib wasadded at 1% w/w. Drug release was measured using RP-HPLC as describedearlier (In vitro drug release assays, TABLE 1 and TABLE 2). The releaseof Sunitinib is shown in FIG. 16 and is characterized by a burst phaseon day 1 with a release of 35% and an extended release phase thatreaches approximately 55% at day 44.

Example 12. Release of Tamsulosin from PEG:PLGA:Diblock Polymeric Paste(50:37:13)

Tamusolin was loaded at 2% w/w to PEG:PLGA:Diblock polymeric paste(50:37:13 PEG:PLGA:Diblock) as described in EXAMPLE 6. Drug release wasmeasured using RP-HPLC as described earlier (In vitro drug releaseassays, TABLE 1 and TABLE 2). The release of Tamsulosin is shown in FIG.17 and is characterized by a burst phase of 47% on day 1. The releasecontinues and reaches 70% by day 6 and 80% on day 21.

Example 13: Release of Lidocaine (8%), Cephalexin (2%) and Ibuprofen(5%) from PEG:PLGA:Diblock Polymeric Paste (50:37:13)

The three drugs were loaded into the paste as previously described inEXAMPLE 3. HPLC analysis for lidocaine, cephalexin and ibuprofen wasperformed using the general chromatographic set up mentioned earlier (Invitro drug release assays, TABLE 1 and TABLE 2). The release of thethree drugs is shown in FIG. 18. Cephalexin was released very quicklyand reached its maximum at 80% on day 3. Lidocaine and Ibuprofen releasewas similar and characterized by a burst release of 54% drug by day oneand a slower drug release over the next 10 to 15 days, reachingapproximately 70% by day 35.

Example 14: Effect of Drug Loaded Polymeric Paste on the Growth of HumanProstate Cancer Tumors in Mice

PEG:PLGA:Diblock polymeric paste (50:37:13) containing docetaxel (1%),bicalutamide (1%), and VPC-27 (4%) was manufactured as previouslydescribed and injected intra-tumorally (see Intratumoral pasteinjection, FIGS. 19A and 19B).

In a different experiment, groups of mice were treated with aformulation containing either docetaxel alone, bicalutamide anddocetaxel, docetaxel and VPC-27 or all three drugs. Treatment groupsthat received both docetaxel and bicalutamide or docetaxel alone showedslower tumor growth and a delayed increase in serum PSA levels thangroups that received pastes that contained also VPC-27.

Example 16: Local Release of Lidocaine and Absence from Serum In Vivo

Five groups of rats (male, Sprague Dawley) with six animals in eachgroup received one injection of paste formulation (0.1 mL)subcutaneously in their flank. The paste formulation was based on a50:50 mixture of PEG300™ and PLGA. Lidocaine was incorporated into thepaste at 80, 100, 120, 140, and 160 mg per g of paste. The correspondingdoses for each group were 23, 29, 36, 40 and 45 mg of lidocaine per kg.Lidocaine dissolved at all concentrations to form a clear paste exceptat the 160 mg/g level, where small crystals were visible that dissolvedwhen warming the paste to 37° C. All formulations were warmed to 37° C.before administration and the injection was smooth.

The concentrations of systemic lidocaine detected in serum were very low(see FIGS. 22A and 22B). The maximum concentrations detected in serum ineach group were all below the upper limit of its therapeutic range of 5μg/mL or 5000 ng/mL in all studied strengths. The maximum serumconcentrations for the 80, 100, 120, 140, 160 mg/g paste formulationswere 557.26±81.15, 578.90±162.59, 638.03±190.61, 855.98±196.18,1148.88±838.97 ng/mL respectively. Since the highest dosing level (160mg/g paste or 45 mg/kg) is 10 times above the locally administeredlidocaine dose in humans (4.5 mg/kg) using a conventional lidocainesolution.

Example 17: Use of Swelling Agents in Paste

Pastes were manufactured using 68% PEG300™, 30% PLGA and 2% of aswelling agent. The agents included carboxymethylcellulose, carbomer orsodium hyaluronate. These pastes were effectively injected through a 5Fureteral catheter of 70 centimeters length. In water there was a clearlyobserved swelling behavior.

The drug gemcitabine was incorporated at 5% (m/m) in the sodiumhyaluronate containing paste. This paste was injected through the 5Fcatheter into the kidney pelvis of a pig. Gemcitabine levels in urinewere initially high and levelled off after 5-7 hours (see FIG. 25A).Serum gemcitabine levels were very low, but detectable in all pigs (seeFIG. 25B). The paste did not result in any blockage of the ureter andpaste fragments were found on the urinary catheter after removal.

Example 18: Use of Swelling Agent, Sodium Hyaluronate, for GemcitabineRelease

Pastes containing 2% of sodium hyaluronate (SH) and increasing amountsof diblock copolymer were prepared to observe swelling and degradationof these pastes over one hour. The inclusion of SH was associated with arapid swelling of the paste in water.

As shown in FIG. 23, pastes with 2% SH were swelling rapidly aftercontact with water. Pastes with 0 and 10% of diblock absorbed less waterthan pastes with higher diblock copolymer content. Furthermore, thesepastes did also not disintegrate over the monitored time. Pastes thatcontained 20, 30 and 40% diblock copolymer immediately absorbed water toroughly double their initial weight. The 20% paste hold its weight atleast over one hour, whereas the 30% and 40% DB pastes lost 30 and 100%of their initial weight over one hour. Overall, a higher amount of DBallows for more rapid water absorption and swelling and quick pastedisintegration.

Example 19. Release of Gemcitabine from Various Polymeric Pastes

As shown in FIG. 24, pastes having no diblock copolymer showed delayedrelease of gemcitabine, except where there was a high PEG 300 level(i.e. 76%) and low PLGA (i.e. 22%). All other compositions showed aburst release at between 0 and 4.5 hours and sustained releasethereafter.

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to an embodiment of the present invention.The invention includes all embodiments and variations substantially ashereinbefore described and with reference to the examples and drawings.

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1.-29. (canceled)
 30. A composition, the composition comprising amixture of the following components: (a) a hydrophobic water-insolublepolymer having an inherent viscosity (IV) of about 0.15 to about 0.5dL/g; (b) a low molecular weight biocompatible glycol; with a molecularweight at or below 1,450 Daltons; and (c) one or more drug compounds orpharmaceutically acceptable salt, solvate or solvate of the saltthereof, wherein the components (a) and (b) do not form covalent bondswith each other, wherein the ratio of the low molecular weightbiocompatible glycol to the hydrophobic water-insoluble polymer isbetween about 70%:30% and about 40%:60%, and wherein the compositionforms a soft implant in an aqueous environment at about 37° C. and thatremains soft.
 31. The composition of claim 30, further comprising adi-block copolymer.
 32. The composition of claim 30, wherein thehydrophobic water-insoluble polymer having an inherent viscosity (IV) ofabout 0.15 to about 0.5 dL/g is polylactic-co-glycolic acid (PLGA). 33.The composition of claim 32, wherein the PLGA has a ratio of lactic acid(LA):glycolic acid (GA) at or below 75:25.
 34. The composition of claim30, wherein the hydrophobic water-insoluble polymer has an inherentviscosity (IV) of about 0.15 to about 0.3 dL/g.
 35. The composition ofclaim 30, wherein the hydrophobic water-insoluble polymer has aninherent viscosity (IV) of about 0.15 to about 0.25 dL/g.
 36. Thecomposition of claim 30, wherein the low molecular weight biocompatibleglycol has a molecular weight between about 76 Daltons and about 1,450Daltons.
 37. The composition of claim 30, wherein the low molecularweight biocompatible glycol is selected from Polyethylene glycol (PEG),methoxypolyethylene glycol (mePEG) and propylene glycol.
 38. Thecomposition of claim 30, wherein the low molecular weight biocompatibleglycol is selected from PEG and mePEG.
 39. The composition of claim 38,wherein the PEG or mePEG has an average molecular weight of between 300Daltons and 1,450 Daltons.
 40. The composition of claim 30, wherein thehydrophobic water-insoluble polymer having an inherent viscosity (IV) ofabout 0.15 to about 0.5 dL/g is PLGA having an LA:GA ratio of 50:50 andthe low molecular weight biocompatible glycol is PEG or mePEG with amolecular weight of about 300 Daltons to about 1,450 Daltons.
 41. Thecomposition of claim 40, wherein the ratio of PEG or mePEG to PLGA isbetween about 60%:40% and about 40%:60%.
 42. The composition of claim41, wherein the ratio of PEG or mePEG to PLGA is between about 60%:40%and about 50%:50%.
 43. The composition of claim 30, wherein the lowmolecular weight biocompatible glycol is PEG
 300. 44. The composition ofclaim 30, wherein the di-block copolymer is between 13% and 26% of thetotal.
 45. The composition of claim 44, wherein the di-block copolymerhas one hydrophobic monomer and one hydrophilic monomer.
 46. Thecomposition of claim 45, wherein the hydrophilic monomer is selectedfrom: PEG; and MePEG; and the hydrophobic monomer is selected from:PLGA; polylactic acid (PLA); Poly-L-lactic Acid (PLLA); andPolycaprolactone (PCL).
 47. The composition of claim 44, wherein thedi-block copolymer is amphiphilic.
 48. The composition of claim 45,wherein di-block copolymer is PLLAmePEG.
 49. The composition of claim30, wherein the one or more drug compounds or pharmaceuticallyacceptable salt, solvate or solvate of the salt thereof is selected fromone or more of the following categories: anti-cancer drugs;anti-inflammatory agents; antibacterial; anti-fibrotic; anesthetic; andanalgesic.
 50. The composition of claim 30, wherein the one or more drugcompounds or pharmaceutically acceptable salt, solvate or solvate of thesalt thereof is hydrophobic.
 51. The composition of claim 30, whereinthe one or more drug compounds or pharmaceutically acceptable salt,solvate or solvate of the salt thereof is hydrophilic.
 52. Thecomposition of claim 49, wherein the anti-cancer drug is selected fromone or more of the following: Actinomycin; All-trans retinoic acid;Azacitidine; Azathioprine; Bleomycin; Bortezomib; Carboplatin;Capecitabine; Cisplatin; Chlorambucil; Cyclophosphamide; Cytarabine;Daunorubicin; Docetaxel; Doxifluridine; Doxorubicin; Epirubicin;Epothilone; Etoposide; Fluorouracil; Gemcitabine; Hydroxyurea;Idarubicin; Imatinib; Irinotecan; Mechlorethamine; Mercaptopurine;Methotrexate; Mitoxantrone; Oxaliplatin; Paclitaxel; Pemetrexed;Teniposide; Tioguanine; Topotecan; Valrubicin; Vemurafenib; Vinblastine;Vincristine; Vindesine; and Vinorelbine.
 53. The composition of claim49, wherein the anesthetic drug is a local anesthetic selected from oneor more of the following: Procaine; Benzocaine; Chloroprocaine; Cocaine;Cyclomethycaine; Dimethocaine/Larocaine; Piperocaine; Propoxycaine;Procaine/Novocaine; Proparacaine; Tetracaine/Amethocaine; Articaine;Bupivacaine; Cinchocaine/Dibucaine; Etidocaine; Levobupivacaine;Lidocaine/Lignocaine/Xylocaine; Mepivacaine; Prilocaine; Ropivacaine;and Trimecaine.
 54. A pharmaceutical composition comprising acomposition of claim 30, together with a pharmaceutically acceptablediluent or carrier.